Benzimidazole has been known as a very important pharmacophore in medicinal and chemical fields. In terms of chemical structure, the compound has a fused form between a benzene ring and an imidazole ring, and has various pharmaceutical characteristics. In the 1990s, numerous benzimidazole derivatives having substituents such as fluoro and propylene were synthesized, and they were shown to have stability, bioavailability and bioactivities.
Recently, with the extremely high prevalence of resistant bacteria, compounds having the structure of benzimidazole have been used as chemotherapeutic agents for treating infections of the resistant bacteria. This is due to the capacity of inhibit the synthesis of bacterial nucleic acids and proteins due to the structure of benzimidazole, which is similar to that of purine. Oxidazol-1H-benzimidazole, as a representative compound, has been known to have antimicrobial activity and has also been reported to have inhibitory activity against fungi as well.
Additionally, benzimidazole derivatives have been developed as HIV inhibitors. One representative example is tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one, which is an antiretroviral agent acting on a particular allosteric binding site of HIV-1 reverse transcriptase. Further, N-alkoxy-2-alkyl-benzimidazole has an EC50 below 600 nM and shows an inhibitory activity on reverse transcriptase with excellent selectivity.
benzimidazole-based compounds having a sulfoxide group and a methylene group are known to inhibit gastric acid secretion by inhibiting a proton pump and protecting gastric mucosa. In addition, benzimidazole-based compounds are also known to have antiviral and antihypertensive effects.
Benzimidazole derivatives are also very useful in the textile industry, and are mainly used as a dye dispersant or a softening agent.
As described above, benzimidazole is a pharmacophore with extremely high applicability in the medicinal and chemical fields, and its synthesis has been developed by numerous research groups and suggested in many documents.
International Publication WO 1997/047603 describes a method of preparing benzimidazole using 2,6-dialkylphenyl as a starting material and International Publication WO 2004/054984 describes a method of preparing the same using 2-amino-3-nitrophenol. However, the above methods use high-cost intermediates and reagents in an amidation reaction, and there is difficulty in purification due to the use of a metal catalyst. Accordingly, the methods are not suitable for conventional large-scale production because they require a high manufacturing cost and the use of a silica gel for separating a certain intermediate.
Additionally, International Publication WO 2007/072146 describes a method of using carbon monoxide in the process of introducing a carbonyl group for amidation reaction. However, the reaction requires an additional reactor and there is a risk of exposure to carbon monoxide during the process.
Accordingly, the inventors of the present invention, while keeping in mind the above problems occurring in the prior art, have discovered a method for preparing benzimidazole, which has been known as a very important pharmacophore in medicinal and chemical fields, with a higher yield than those of the conventional methods and also enabling a large-scale production in industry while using conventionally-available reagents and solvents with a low manufacturing cost.